Download - Fatty liver
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THE EPIDEMIOLOGY, PATHOGENESIS AND HISTOPATHOLOGY OF FATTY
LIVER DISEASE
Adam P Levene and Robert D GoldinDepartment of Histopathology,
Imperial College Faculty of Medicine at St Mary’s Hospital,London.UK(Histopathology 2012, 61, 141-152)
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INTRODUCTION
• Fatty liver disease consists of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), with a subset of these groups developing alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatits (NASH), respectively.
• The increasing prevalence of obesity and diabetes, and the associated metabolic syndrome is leading to an increased incidence of NAFLD.
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• The increasing prevalence of NAFLD is particular worrying because patients appear to have a higher mortality from non-liver related and recent data have also highlighted an increased risk for cardiovascular disease.
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• Underlying pathogenesis of NAFLD is still incompletely understood.
• Majority of patients with NAFLD have a stable disease, with isolated steatosis and an indolent course with no progression to advanced liver disease or clinical sequelae.
• However, a subset develop NASH and are at risk progressive fibrosis, cirrhosis and liver failure, or hepatocellular carcinoma (HCC).
• The distinction between isolated steatosis and NASH is important, as their prognoses and management are different
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• The gold standard for identification of patients with NASH is liver biopsy.
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EPIDEMIOLOGY AND DISEASE NATURAL HISTORY
NAFLD:
• Estimates of NAFLD prevalence based on ‘cryptogenic’ abnormal liver function test results, autopsy samples, ultrasound and magnetic resonance spectroscopy range between 3% and 37%, with the usual figure quoted being around 30%.
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• Studies suggest that ethnic background plays a role in the incidence of NAFLD were provided by a study that revealed a significantly higher prevalence of NAFLD in Hispanics than in non-Hispanic whites, even after controlling for obesity and body fat distribution.
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• Studies show that NAFLD is not always associated with raised alanine transaminase (ALT) or gamma-glutamyl transpeptide positivity.
• NAFLD was more likely in the presence of obesity, hyperglycemia,hyperinsulinaemia, hypertriglyceridaemia, and systolic hypertension, all features of the metabolic syndrome.
• Although total fat consumption is not significantly associated with the risk of cirrhosis or liver cancer, cholesterol consumption is.
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• Recent clinical and experimental studies have shown that coffee protects the liver against the development of fat-induced liver damage.
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• The prevalence of NASH is difficult to determine, as large population-based studies are not possible, because a liver biopsy is still, currently, required for diagnosis.
• An autopsy study found NASH in 18.5% of markedly obese patients and 2.7% of lean patients.
• This highlights the possible effect that weight has on the incidence of NASH.
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Normal liver
Fatty liver
NASH
Progressive fibrosis
cirrhosis
Liver failure Liver cell cancer
Stable disease
30%
30%
20%
0-10%30-40%
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• A well recognized complication of cirrhosis resulting from NAFLD is HCC.
• HCC has also been noted as a rare complication of NAFLD prior to cirrhosis.
• This may be explained by the association of diabetes and obesity with the development of HCC, as well as the carcinogenic factors associated with cirrhosis in general.
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ALD:
• Studies in unselected heavy drinkers of alcohol suggest that 80% develop steatosis, which is the earliest and most common histopathological manifestation of ALD.
• Steatosis occurs in most people consuming alcohol in excess of 80 g/day, and can resolve within 2-4 weeks of abstinence.
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Normal liver
Fatty liver
ASH
fibrosis
cirrhosis
Alcohol intake Alcohol abstinence?Abstinence effect
80%
20-40%
40%
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• Severe ASH has a very poor prognosis, whereas patients with mild and moderate ASH can improve with abstinence.
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• It is extremely difficult to predict histological stage clinically in ALD patients before the development of decompensated cirrhosis.
• A small subset of ALD patients presenting with decompensated chronic liver disease has severe ASH without cirrhosis on biopsy.
• Conversely, some ALD patients who are clinically well but have abnormal liver function test results and undergo liver biopsy are found to have advanced ALD with severe ASH.
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• Staging Of ALD is most accurately performed histologically by performing liver biopsy, which may need to be via the transjugular route in patients with impaired clotting.
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PATHOGENESIS
NAFLD:
• NAFLD is closely linked to obesity, insulin resistance, and the metabolic syndrome.
• The initial theory for the pathogenesis of NAFLD was the ‘two-hit’ hypothesis.
• The first hit, steatosis, sensitives the liver to the induction of inflammation by a second insult that promotes oxidative stress and steatohepatitis.
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• This model has subsequently been revised, in recognition that a combination of ‘second hits’ (both environmental and genetic) may lead to the development of steatohepatitis.
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• Currently, it is not fully understood why some patients develop isolated steatosis and others develop steatohepatitis.
• However, it appears that insulin resistance and increased levels of free fatty acids in the liver are strongly associated with NASH.
• When insulin resistance develops, free fatty acids are inappropriately moved to non-adipose tissues such as the liver by decreased inhibition of lipolysis and increased de novo lipogenesis.
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• There is currently increasing work on the interaction between cytokines and adipokines (cytokines secreted by adipose tissue) in an attempt to understand the mechanisms involved in NAFLD development.
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• Insulin resistance is thought to be regulated by proinflammatory cytokines, such as tumour necrosis factor-a (TNF-a), and adipokines such as adiponectin and leptin.
• Oxidative stress and apoptosis also appear to contribute to the development and progression of NASH.
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ALD:
• Pathogenesis is still incompletely understood.
• Recent discoveries - Many pathways leading to oxidative stress, and the new mechanism of endoplasmic reticulum stress.
• There are many similarities with NAFLD, such as the proinflammatory cytokine TNF-a and the adipokines adiponectin and leptin.
• Obesity being implicated as a risk factor for the development of ASH and cirrhosis in people with heavy alcohol consumption.
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HISTOPATHOLOGY
NAFLD
• Histological analysis of a liver biopsy remains the gold standard for and only accurate way of assessing the degree of steatosis, necroinflammatory changes and fibrosis of NASH, and therefore distinguishing NASH from isolated steatosis.
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• The pathology committee of the NASH CRN group developed and histological scoring system for use in NAFLD.
• For each case, an NAFLD activity score (NAS) and a separate fibrosis stage was given.
• The NAS comprised 14 histological features, nine of which were recorded as present or absent (such as Mallory-Denk bodies), and three of which were semiquantitatively [steatosis (0-3), lobular inflammation (0-3), and hepatocellular ballooning (0-2)], to give a score of between 0 and 8.
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Steatosis grade (0-3) Lobular inflammation (0-3) Hepatocyte ballooning (0-2)
0: <5% 0: None 0: None
1: 5-33% 1: <2 foci/*20 field 1: Mild, few
2: 34-66% 2: 2-4 foci/*20 field 2: Moderate-many
3: >66% 3: >4 foci/*20 field
NAFLD activity score (NAS): 0-8 0-2 not NASH
3-4 uncertain for NASH
5-8 NASH
Non-alcoholic steatohepatitis (NASH) Clinical Research Network Fibrosis Staging System
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Fibrosis: based on the use of Masson’s trichrome stain
0: None
1a: Mild zone 3 perisinusoidal fibrosis Requires trichrome stain to identify
1b: Moderate zone 3 perisinusoidal fibrosis May be appreciated on haemotoxylin and eosin
1c: Portal fibrosis only
2: Zone 3 perisinusoidal fibrosis andd periportal fibrosis
3: Bridging fibrosis
4: Cirrhosis
Non-alcoholic steatohepatitis (NASH) Clinical Research Network Fibrosis Staging System
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• The lobular inflammatory infiltrate is usually composed predominantly of neutrophils, but lymphocytes and macrophages are commonly seen.
• In practice, the presence of ballooned hepatocytes is a sine qua non for the diagnosis of NASH rather than steatosis.
• In a meticuluos histological study, serial staining consistently demonstrated that hepatocellular ballooning was associated with fat droplets, as shown by oil red O positivity and CK-18-positive Mallory-Denk bodies.
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• Histological features recorded but not scored in NAS include Mallory-Denk bodies, megamitochondria, and nuclear vacuolation.
• In NAFLD, Mallory-Denk bodies are often small and poorly formed, and may be difficult to detect in routinely stained sections.
• Immunohistochemistry for ubiquitin, p62, CK-8 and CK-18 can be used to demonstrate antigens associated with Mallory-Denk bodies and ballooned hepatocytes.
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• Summary, Histological spectrum of NAFLD is characterized by steatosis, lobular inflammation, ballooning of hepatocytes, fibrosis, and other features that may or may not be present, such as Mallory-Denk bodies and portal inflammation.
• The NASH CRN grading and staging system of NASH is based on the use of haematoxylin and eosin and Masson’s trichrome stain, so it can be used routinely by histopathologies.
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Nonspecific steatosis, predominantly macrovesicular, with occasional foci of inflammatory cells in the hepatic lobules and many hepatocytes with glycogenated nuclei (H&E, ×200).
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Steatohepatitis with several hepatocytes showing ballooning degeneration intermixed with steatosis and foci of inflammatory cells in the hepatic lobules (H&E, ×200).
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Mallory hyaline showing eosinophilic and ropy inclusions in the cytoplasm (H&E, ×400).
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Perivenular/pericellular fibrosis in zone 3 (Masson trichrome, ×200).
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ALD:
• The diagnosis of ALD is usually easy to make with a clear history of excessive alcohol consumption and negative markers for other chronic liver diseases.
• However, one needs to remember that the liver disease seen in patients who drink excessively is not always caused by alcohol
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• The role of Liver biopsy in ALD is controversial but it is still the gold standard investigation and used to
• clarify cases with an unusual clinical course,
• to better define the contribution of alcohol in patients with possible non-alcohol-related comorbidity (e.g. in hepatitis C or use of lipid-lowering medications),
• and in some patients, to determine the severity of liver disease.
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• It can also be used to specifically assess the amount neutrophils within the liver parenchyma to act as a guide to whether the patient would benefit from steroid treatment.
• Liver biopsy is not used in advanced ALD where there is evidence of decompensated cirrhosis, as the risk outweigh any potential benefits.
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• The histopathology of ALD is similar to that of NAFLD, and occurs mainly in the liver parenchyma in the perivenular areas.
• Characteristic early lesions in ALD include perivenular and pericellular fibrosis.
• The development of ASH is dominated by a neutrophilic infiltrate, ballooning degeneration, Mallory-Denk bodies, and hepatocyte necrosis.
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• In most cases, a distinction between ALD and NAFLD cannot be made on morphological criteria and the diagnosis has to rely on clinicopathological correlation.
• Overall features in favour of ALD include canalicular cholestasis, cholangiolitis, florid zone 3 changes such as dense infiltration by neutrophils, prominent Mallory-Denk bodies, and extensive zone 3 fibrosis associated with sinusoidal obliteration and hepatic veno-occlusive lesions.
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• NAFLD tends to have more marked steatosis and less severe steatohepatitis changes
• One of the most helpful changes, and one that strongly favours NAFLD, is nuclear vacuolation, which is seen in 70-80% of NAFLD cases and in only 5-10% of ALD cases.
• The glycogenated nuclei can be seen in NAFLD-related cirrhosis even when other changes of NASH have disaappeared.
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• Immunohistochemistry for protein tyrosine phosphate 1B (PTP1B) and insulin receptor on hepatocytes has been suggested to be useful in differentiating NAFLD from ALD.
• PTP1B was shown to be upregulated in the cytoplasm of hepatocytes in NASH biopsies as compared with ASH biopsies.
• Insulin receptor showed loss of membranous staining in hepatocytes from NASH biopsies, but was still present on ASH biopsies.
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CONCLUSION• NAFLD and ALD are increasingly common and
recognized diseases.
• The risk factors and possible courses of the two diseases are well known, with many areas of ovelap, although it is still unclear why some people progress to NASH/ ASH and cirrhosis and others do not.
• There is an increasing knowledge of the pathogenesis of both diseases.
• In NAFLD especially, and in ALD to a lesser degree, liver biopsy and histopathological assessment are key for determining whether a patient has steatosis or steatohepatitis, and also for assessing the degree of liver damage and fibrosis.
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